We use both cancer cell lines and primary tumors to identify genetic and epigenetic factors that are important in breast cancer progression and metastases. We have conducted comprehensive genetic characterization of 161 primary tumors as well as four isogenic cell lines, representing different stages of tumor progression. Similar to mountain and hill view of mutations, gene amplification also showed high and low frequency alterations in breast cancers. The frequently amplified genes include the well-known oncogenes, ERBB2, FGFR1, MYC, CCND1, PIK3CA whereas infrequent amplified oncogenes include CCND2, EGFR, FGFR2, POLD3, FGFR1, and NOTCH3. Gene expression signature from a 4-gene cluster containing POLD3, CCND1, FGFR1, and FGFR2 can predict breast cancer survival in multiple data sets. We also conducted DNA copy number analysis using MCF10A, a normal immortalized cell line, and cancer cells derived from MCF10A. Our study identified multiple genetic alterations that delineate tumor transformation and metastasis. We found that MYC amplification and homozygous deletion at CDKN2A locus were already present in MCF10A. The cancer cell lines, MCF10Ca1h and MCF10CA1a, acquired additional genetic alterations including PIK3CA mutation as well as gain of chromosome 3 containing the mutant PIK3CA allele. Furthermore, we found that the concomitant PIK3CA activation and amplification also occurred in primary tumors. We are currently investigating global DNA methylation changes in breast tumors and the role of allelic variation in gene expression and epigenetic modification in human cancers. Our genetic and epigenetic analyses of breast primary tumors and cancer cell lines provided a coherent picture about corroborating events that drive the breast cancer progression.